Signal transduction Activin A signaling regulation
Activin A signaling regulation
Activins are members of the Transforming growth factor beta (TGF-beta) superfamilythat participate in regulation of several biological processes, including celldifferentiation and proliferation, apoptosis and immune response [1], [2], [3].
There are different types of Activins [4], but the role of ActivinA has been the most extensively studied by far.
Like most members of the Transforming growth factor beta superfamily, Activin Amediates its biological effects through complex of transmembrane receptorserine/threonine kinases. Activin A initially binds to Activin A receptors type II( ActRIIA or ActRIIB ) and then recruitsActivin A receptor, type IB (ALK-4 ) [2], [5].
ALK-4 interacts with and phosphorylates adaptors of SMAD family member 2 and 3( SMAD2 and SMAD3 ). Subsequently, SMAD family member 4 ( SMAD4 )bounds to phosphorylated SMAD2 and SMAD3 and this complex is translocatedto the nucleus [2]. After translocation into the nucleus, SMAD2 andSMAD3 may activate transcription of different genes.
Regulation of Activin A signal occurs at the extracellular, membrane,cytoplasmic and nuclear levels [6], [2].
Activin A signaling may be inhibited by extracellular proteinsFollistatin and Follistatin-like 3 ( FSRP ). Follistatin andFSRP bind to Activin A with high affinity, and their binding is nearlyirreversible. Activin A in the complex with Follistatin s is impeded thebinding to ActRIIA or ActRIIB [7], [8].
Inhibin is another extracellular Activin A inhibitor. The association ofActRIIA or ActRIIB with Inhibin and TGF-beta receptor type III(betaglycan) prevents access of Activin A to the receptor and therefore leadsto a competitive inhibition of Activin A signaling [9], [4], [8].
Moreover, some membrane proteins inhibit Activin A signal via repression ofALK-4. Immunoglobulin superfamily, member 1 ( IGSF1 ) [10] andBMP and activin membrane-bound inhibitor homolog ( BAMBI ) [11] form acomplex with the ALK4, which then attenuates Activin A -stimulatedreporter gene activity [10].
In addition, FK506 binding protein 1A 12kDa ( FKBP12 ) may recruit theSMAD7/ SMAD specific E3 ubiquitin protein ligase 1 ( SMURF1 ) complex toALK-4 and enhance ubiquitination of the receptor [12]. It has beenshown that SMAD7 stably interacts with ALK-4 directly and inhibits it[13]. SMAD7 expression is upregulated by activin, representingauto-inhibitory feedback mechanism of ligand-induced signaling [6].
Several transcriptional co-repressors, such as Distal-less homeobox 1 ( DLX1 )[14], Ecotropic viral integration site 1 ( Evi-1 ) [15]and LEM domain containing 3 ( MAN1 ) [16], [17] interactwith SMAD s and inhibit them directly.
Activin A signal may be stimulated by different activators, such as, Forkheadbox H1 ( FAST-1/2 ) [18] and Positive cofactor 2 ( PC2 (TIG1) )[19]. FAST-1/2 -dependent transcription may be inhibited by Forkheadbox G1 ( FKHL1 ) [20].
Another pathway regulated by Activin A signaling is acetylation/deacetylationof SMAD s and different Histone s at Activin A -dependent promoters.For example, V-ski sarcoma viral oncogene homolog ( Ski ) may inhibit SMAD3/ SMAD4 - dependent transcription by recruiting Histone deacetylase 1 (HDAC1 ) [21], [2]. E1A binding protein p300 ( p300)/ CREB binding protein ( CBP ) may activate Activin A signaling byacetylation of SMAD s and Histone s [6], [22]
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